Multi-centre trials in Orthopaedic Oncology: Dream or Reality?
Michelle Ghert, MD, FRCSC Associate Professor Department of Surgery
McMaster University
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22 year-old male with sarcoma right femur
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Deep infection in total joints Approximately 1% risk AAOS
guidelines: 24 hours of gram positive coverage with pre-operative
dosing
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Tumour prosthesis: higher risk Patients are myelo-depleted due
to chemotherapy Surgeries are long and the wound is open for
several hours Large foreign body Large dead space Loss of
protective soft-tissue coverage
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What is the magnitude of the problem?
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Systematic Review Deep infection rate 9.5% (95% confidence
interval: 8.1% to 11%) Comparison to primary arthroplasty: 1%
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Systematic Review Conclusions The risk for deep infection
following tumour prosthesis is high, X10 that of total joints
Antibiotic regimens vary from publication to publication There no
published guidelines to direct management
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What antibiotic regimens do we use?
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Duration of antibiotics Table 2: Length of Time Prophylactic
Antibiotics Prescribed Following Long-bone Reconstruction Type of
Reconstruction24 hrs48 hrs3-7 daysUntil Suction Drain Removed Tumor
prosthesis25 (35.7%)13 (18.6%)3 (4.3%)29 (41.4%) Allograft18
(26.5%)13 (19.1%)11 (16.2%)26 (38.2%) Allograft-prosthesis
composite17 (25.4%)12 (17.9%)9 (13.4%)29 (43.3%)
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Results
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PARITY Survey conclusions Practice patterns vary considerably
with respect to antibiotic regimen, dosages and duration Majority
of surgeons are willing to change practice Overwhelming support for
a multi-centre clinical trial
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Hierarchy of Evidence Randomized Trials Prospective Cohort
Studies Retrospective Case Series Case Control Studies Opinion
Level 1 Level 2 Level 3 Level 4 Level 5 Less Bias More Bias
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RCTs in Orthopaedic Oncology Orthopaedic Oncology multi-center
randomized controlled trials: Radiation Oncology: one trial, 150
patients Medical Oncology: 72, methodologically poor Surgical
Oncology: NONE There is a lot of talk about RCTs in Orthopaedic
Oncology, but no doing
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Why do we need multi-centre trials?
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Tibial Shaft Fractures (SPRINT)
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Multicenter RCTs Advantages Level 1 Evidence more centers =
More Patients shorter study recruitment time increased
generalizability of results collaboration between centers,
countries and continents
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Multicenter RCTs Disadvantages They are Hard to Do Complex
organization Very Expensive
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But not impossible. Cardiology OASIS-6 RCT 13000 pts (JAMA,
2006) 447 hospitals 41 countries
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But not impossible. Intensive Care Medicine PROTECT (DVT
prophylaxis) Canadian Critical Care Trials Group 4000 pts North
America/Australia
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But not impossible Neonatal Medicine Trial of Indomethacin
Prophylaxis in Preterms (TIPP) Investigators. N=910 infants 32
centers NA, Austalia, NZ, China JAMA. 2003
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Has it been done in Orthopaedic Surgery? SPRINT Trial (Tibial
Shaft Fractures) 1339 patients recruited, 95% F/U
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Challenges in Surgical Trials
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Can Surgeons be Blinded?
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Who can be blinded? Patient and outcome assessors
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Expertise Bias
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Surgeons tend to stick to procedures that they are good at
Difficult to convince surgeons to develop new techniques Solution:
patients are allocated to provider, not procedure
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But can it be done anyways?
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Center for Evidence-Based Orthopaedics
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SPRINT trial: 1339 patients, 95% follow-up FLOW trial: 2200
patients recruited, target 2200 FAITH trial: 900 patients, target
1000 TRUST trial: 600 patients, target 1000 HEALTH trial: 350
patients, target 1400 INORMUS and PRAISE prospective studies: 9000
patients All trials are funded by NIH/CIHR 150 centers around the
world
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PARITY Objective: To evaluate the efficacy of short- vs.
long-term post-operative prophylactic antibiotic regimens on the
incidence of deep infection following endoprosthetic reconstruction
of lower extremity bone tumors
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Study Design PARITY is a multi-center randomized controlled
trial using a parallel two- arm design
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Patient screened and eligible and provides informed consent
Randomization Standard pre-op and intra-op antibiotics AND 24 hours
post op antibiotics Standard pre-op and intra-op antibiotics AND 5
days post op antibiotics Follow-up one year
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Eligibility Criteria Lower extremity tumour prosthesis Skeletal
maturity Primary bone malignancy or benign aggressive tumor
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Exclusion Criteria MRSA or VRE colonization Allergy to PCN or
Ancef [cefazolin] Previous local surgery (excluding biopsy)
Previous local infection Systemic infection
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Randomization 24-hour computer randomization
(www.randomize.net) Pharmacist will randomize patient Stratified
based on center and tumor location (femur or tibia)
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Blinding Patients, nurses, research staff, surgeons and central
adjudication committee (CAC) blinded Only pharmacist will be aware
of treatment allocation
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Primary outcome and adjudication Deep infection as defined by
CDC 1992 Within one year of surgical implantation CAC: 2
Orthopaedic Surgeons and 1 Infectious Disease specialist Global
Adjudicator Platform
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Secondary Outcomes MSTS-87 and -93 TESS Antibiotic-related
complications
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Data Management
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STEERING COMMITTEE Overall responsibility for the trial CENTRAL
ADJUDICATION COMMITTEE Review and classification of all clinical
events DATA MONITORING COMMITTEE Review of adverse events and
stopping rules based on benefit and harm METHODS AND COORDINATING
CENTRE Data management, daily conduct of the trial PARTICIPATING
CLINICAL CENTRES Patient recruitment and follow-up as per study
protocol PARITY Trial Organization Center for Evidence-Based
Orthopaedics
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Steering Committee Dr. Michelle Ghert (McMaster University) Dr.
Ben Deheshi (McMaster University) Dr. Mohit Bhandari (McMaster
University) Dr. Tim OShea (McMaster University) Dr. Jay Wunder
(University of Toronto) Dr. Lor Randall (Huntsman Cancer Institute,
Utah) Dr. Lehana Thabane (McMaster University) Dr. Ginger Holt
(Vanderbilt University) Dr. Gordon Guyatt (McMaster
University)
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STEERING COMMITTEE Overall responsibility for the trial CENTRAL
ADJUDICATION COMMITTEE Review and classification of all clinical
events DATA MONITORING COMMITTEE Review of adverse events and
stopping rules based on benefit and harm METHODS AND COORDINATING
CENTRE Data management, daily conduct of the trial PARTICIPATING
CLINICAL CENTRES Patient recruitment and follow-up as per study
protocol PARITY Trial Organization Center for Evidence-Based
Orthopaedics
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Central Adjudication Committee Dr. Ben Deheshi (McMaster
University) Dr. Michelle Ghert (McMaster University) Dr. Tim OShea
(McMaster University) Dr. Lor Randall (Huntsman Cancer Institute,
Utah)
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STEERING COMMITTEE Overall responsibility for the trial CENTRAL
ADJUDICATION COMMITTEE Review and classification of all clinical
events DATA MONITORING COMMITTEE Review of adverse events and
stopping rules based on benefit and harm METHODS AND COORDINATING
CENTRE Data management, daily conduct of the trial PARTICIPATING
CLINICAL CENTRES Patient recruitment and follow-up as per study
protocol PARITY Trial Organization Center for Evidence-Based
Orthopaedics
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Data Safety Monitoring Board Dr. Peter Rose, Chair (Mayo
Clinic) Dr. Brian Brigman (Duke University Medical Center) Dr.
Vikram Venkateswaran (Georgetown, Ontario)
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Power analysis Infection rate mean 9.5% Superiority of
long-term antibiotics: threshold of 5% for inferiority Alpha 5%,
Power 80% 431 patients per arm (862 total) Estimated sample size of
908 to account for 5% loss to follow-up, errors, drop-out etc
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SPRINT trial: 1339 patients, 95% follow-up FLOW trial: 2200
patients recruited, target 2200 FAITH trial: 900 patients, target
1000 TRUST trial: 600 patients, target 1000 HEALTH trial: 350
patients, target 1400 INORMUS and PRAISE prospective studies: 9000
patients All trials are funded by NIH/CIHR 150 centers around the
world
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Pilot: Feasibility Assess recruitment 10% of definite trial:
100 patients in 12 months Maintain follow-up (95%) and data quality
Assess ability to accurately use internet-based randomization
system Ensure compliance
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Funding Orthopaedic Research & Education Foundation: PARITY
has been awarded an OREF/MSTS Clinical Research Grant in
Orthopaedic Oncology. PSI Foundation: PARITY has also received
funding from the Physicians Services Incorporated Foundation
Private Donation: Sarcoma Fund Canadian Cancer Society Research
Institute Innovation Grant
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Active Sites (O7 Feb 2013) Canada *Juravinski Hospital &
Cancer Centre, Hamilton, Ontario, Canada *Mount Sinai Hospital,
Toronto, Ontario, Canada *Ottawa Hospital, Ottawa, Ontario, Canada
*McGill University Health Centre, Montreal, Quebec, Canada *Hopital
Maisonneuve Rosemont, Montreal, Quebec, Canada Franois dAssise et
LHotel-Dieu de Quebec, Quebec City, Quebec, Canada *Vancouver
General Hospital, Vancouver, British Columbia, Canada USA
*Vanderbilt Medical Centre, Nashville, Tennessee, USA Beth Israel
Deaconess Medical Centre, Boston, Massachusetts, USA Boston
Childrens Hospital, Boston, Massachusetts, USA *Huntsman Cancer
Institute, Salt Lake City, Utah, USA Memorial Sloan-Kettering
Cancer Centre, Cornell, New York, USA UK The Royal Orthopaedic
Hospital NHS Foundation Trust, Birmingham, UK The Royal National
Orthopaedic Hospital NHS Trust, Stanmore, UK The Robert Jones Agnes
Hunt Hospital NHS Foundation Trust, Oswestry, UK Oxford University
Hospital NHS Trust (Nuffield Orthopaedic Centre), Oxford UK The
Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle UK
Argentina Hospital Universitario Austral, Beuonos Aires, Argentina
*actively enrolling Interested sites Canada Halifax USA Albany
Medical College, Albany, New York, USA Menorah Medical Center and
Mid American Sarcoma Institute, Overland Park, Kansas, USA Marshall
University, Huntington, West Virginia University of Washington,
Washington, USA International University Hospital of Tampere,
Tampere, Finland Tel Aviv Medical Centre, Tel Aviv, Israel Nagoya
University, Chikusa-ku, Nagoya, Japan Cancer Institute Hospital
& the Japanese Foundation for Cancer Research, Toyko,
Japan
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Launch Sept 28 th 2012 Toronto
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PARITY International
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To boldly go
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Multi-centre trials in Orthopaedic Oncology: Dream or Reality?
Michelle Ghert, MD, FRCSC Associate Professor Department of Surgery
McMaster University
